The heparan sulfate proteoglycan syndecan‐1 regulates colon cancer stem cell function via a focal adhesion kinase—Wnt signaling axis

• DOI: 10.1111/febs.15356
• Publication Date: 2020-05-05T07:28:44Z
• Authors: Sampath Kumar Kat...; Valeria Tria; Wey‐Cheng Sim; George W. Yip; Stefano Molgora; Theodoros Karnavas; Eslam A. Elghonaimy; Paride Pelucchi; Eleonora Piscitelli; Sherif Abdelaziz ...; Ileana Zucchi; Rolland Reinbold; Burkhard Greve; Martin Götte
• Keywords: 0301 basic medicine; Indoles; extracellular matrix; Kruppel-Like Transcription Factors; tumor-initiating cells; Biochemistry; Aldehyde Dehydrogenase 1 Family; Mice; 03 medical and health sciences; Cell Movement; glycosaminoglycan; Animals; Humans; AC133 Antigen; Benzothiazoles; xenograft; European Commission; Molecular Biology; Knowmad Institut; Cell Proliferation; H2020 Marie Skłodowska-Curie Actions; EC; Integrin beta1; H2020; RISE; Cell Biology; Nanog Homeobox Protein; syndecans; Epithelial Cell Adhesion Molecule; 3. Good health; Gene Expression Regulation, Neoplastic; Focal Adhesion Kinase 1; Colonic Neoplasms; Neoplastic Stem Cells; Caco-2 Cells; HT29 Cells; Oligopeptides

In colon cancer, downregulation of the transmembrane heparan sulfate proteoglycan syndecan‐1 (Sdc‐1) is associated with increased invasiveness, metastasis, and dedifferentiation. As Sdc‐1 modulates signaling pathways relevant to stem cell function, we tested the hypothesis that it may regulate a tumor‐initiating cell phenotype. Sdc‐1 small‐interfering RNA knockdown in the human colon cancer cell lines Caco2 and HT‐29 resulted in an increased side population (SP), enhanced aldehyde dehydrogenase 1 activity, and higher expression of CD133, LGR5, EPCAM, NANOG, SRY (sex‐determining region Y)‐box 2, KLF2, and TCF4/TCF7L2. Sdc‐1 knockdown enhanced sphere formation, cell viability, Matrigel invasiveness, and epithelial‐to‐mesenchymal transition‐related gene expression. Sdc‐1‐depleted HT‐29 xenograft growth was increased compared to controls. Decreased Sdc‐1 expression was associated with an increased activation of β1‐integrins, focal adhesion kinase (FAK), and wingless‐type (Wnt) signaling. Pharmacological FAK and Wnt inhibition blocked the enhanced stem cell phenotype and invasive growth. Sequential flow cytometric SP enrichment substantially enhanced the stem cell phenotype of Sdc‐1‐depleted cells, which showed increased resistance to doxorubicin chemotherapy and irradiation. In conclusion, Sdc‐1 depletion cooperatively enhances activation of integrins and FAK, which then generates signals for increased invasiveness and cancer stem cell properties. Our findings may provide a novel concept to target a stemness‐associated signaling axis as a therapeutic strategy to reduce metastatic spread and cancer recurrence.DatabasesThe GEO accession number of the Affymetrix transcriptomic screening is GSE58751.